Journal
NEUROPHARMACOLOGY
Volume 39, Issue 10, Pages 1920-1928Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0028-3908(00)00015-0
Keywords
rapamycin; FK506; FKBP-12; whole-cell recording; long-term potentiation; pairing stimulation
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Immunophilin-CsA and FK506 complexes bind to calcineurin (CaN) and inhibit its phosphatase activity leading to enhancement of neuronal activities. However, inhibition of CaN activity is not the mediator of modulatory activity for IP3 and ryanodine receptors and does not mediate the neurotrophic actions of FK506. FK506 binding protein (FKBP)-12 also binds rapamycin, another immunosuppressant which does not affect CaN activity. Using whole-cell patch clamp techniques, excitatory postsynaptic currents (EPSCs) were recorded and we analyzed the effect of immunosuppressants on the synaptic potentiation induced by pairing weak presynaptic stimulation with postsynaptic depolarization in CA1 neurons of rat hippocampal slices. We found that postsynaptic application of rapamycin or FK506, at low concentrations, but not cyclosporin A, in conjunction with weak pairing stimulation, induced NMDA-dependent long-term potentiation (LTP). The rapamycin-induced LTP was blocked by chelating intracellular Ca2+ or by inhibiting the intracellular Ca2+ release. Thus, Ca2+ release from intracellular Ca2+ stares is required for the induction of LTP by weak pairing stimulation in the presence of rapamycin or FK506 at postsynaptic sites. We propose that postsynaptic FKBP-12 regulates synaptic transmission by stabilizing the postsynaptic Ca2+ signaling mechanism in rat hippocampal CA1 neurons. (C) 2000 Elsevier Science Ltd. All rights reserved.
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